Researchers at the Centers for Disease Control and Prevention (CDC) estimated that as many as 47 million Americans may exhibit a cluster of medical conditions (a “metabolic syndrome”) characterized by abdominal obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, high blood pressure, and elevated fasting blood glucose [1]. Having three or more traits of metabolic syndrome significantly increases the risk of dying from coronary heart disease or cardiovascular disease. It has also been reported that patients with even one or two metabolic syndrome traits, or those with metabolic syndrome but without diabetes also were at increased risk for death from coronary heart disease or cardiovascular disease.
Obesity and atherosclerosis have a major impact on morbidity and mortality in the United States and many other countries. Elevated cholesterol, particularly low-density lipoprotein (LDL) cholesterol, is a major risk factor for atherosclerosis. Thyroid hormone replacement in hypothyroid individuals reduces total cholesterol and LDL-cholesterol [2-4]. An excess of thyroid hormone in thyrotoxicosis causes weight loss. The weight loss consists not only of fat but also muscle mass and even myopathy can be observed [5].
The ability of thyroid hormone to lower cholesterol when given to hypothyroid individuals prompted efforts to design analogs that take advantage of these properties in the treatment of hypercholesterolemia. This action is the result of an accelerated LDL-cholesterol clearance rate [6-8]. T3 increases levels of both the hepatic LDL receptor [9] and its mRNA [10]. Additional thyroid hormone actions on lipid metabolism include increasing the activity of lipoprotein lipase [11].
Numerous studies have been carried out to synthesize thyroid hormone analogs that mimic the actions of the natural hormones. The objective of most of these efforts has been to develop thyromimetics that lower plasma cholesterol without adverse cardiac effects. A series of thyroxine analogs and methods of synthesis are described in U.S. Pat. No. 3,109,023. Thyroid hormone agonists that are highly selective for the thyroid hormone receptor (TR) β-subtype are described in U.S. Pat. No. 5,883,294 and WO 00/39077. U.S. Pat No. 5,284,971 describes a class of thyromimetics, which have the distinguishing characteristic of a sulfonyl bridge in the diphenyl core.
The usual method employed in treating obesity has been reduction of caloric intake either by reduced caloric diet or appetite suppression. An alternative method is to stimulate metabolic rate in adipose tissue. For example U.S. Pat Nos. 4,451,465, 4,772,631, 4,977,148 and 4,999,377 disclose compounds possessing thermogenic properties at dosages causing few or no deleterious side-effects, such as cardiac stimulation. Further pharmaceutical compositions including those selective for the β-type thyroid hormone receptor have been taught by Cornelius et al. in US 2002/0035153 A1. A representative compound of this type, N-[4-[3′[(4-fluorophenyl)hydroxymethyl]-4′-hydroxyphenoxy]-3,5-dimethylphenyl]oxamate (CGS-26214) reportedly is devoid of significant cardiovascular effects but possess significant thermogenic properties. Accordingly, CGS-26214 and related compounds are useful in the treatment of obesity and related conditions in humans and companion animals. According to Cornelius et al. compounds related to CGS-26214 may be combined with an anorectic agent such as phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a Neuropeptide Y antagonist, a cholecystokinin-A agonist, etc. Whereas administration of a selective β-agonist would compensate for endogenous hormones in terms of TRβ stimulation it may not significantly activate TRα, which could cause a relative hypothyroidism or could cause increased hepatic toxicity. Also, there is no information on whether weight loss would be selective for fat or would include muscle as well.
Goglia and Lanni in W02005009433 describe the use of a breakdown product of thyroid hormone (3,5-diiodothyronine) as a regulator of lipid metabolism to stimulate burning of fatty acid in mitochondria. T3, which is largely derived from T4 by the action of monodeiodinases, has been thought to be the major active form of thyroid hormone. It has been reported that 3,5-diiodothyronine (3,5-T2) is able to directly increase mitochondrial respiration by increasing the burning of fatty acids. In keeping with the stimulation of mitochondrial respiration, fatty acid oxidation rate was increased by 3,5-T2. In rats fed a high-fat diet long-term treatment with 3,5-T2 reportedly decreased weight gain. These effects were observed without suppression of TSH or evidence of hyperthyroidism. 3,5-T2 also was given to four volunteers in daily doses between 15 and 90 microgram/kg. There was a reduction in plasma levels of triglycerides from 140-70 mg/dL and cholesterol from 241 mg/dL to 210 mg/dL. The resulting metabolic rate increased in a dose dependent manner reaching a maximum increase of 40% (from 1770 Kcal to 2400 Kcal per day). Fat mass was reduced in the range of 10 to 15%. There was no significant change in plasma levels of free T3 and free T4.
The actions of 3,5-T2 and T3 on mitochondrial respiration can be distinguished by differences in the time course of the response [12]. Changes in resting metabolic rate in hypothyroid rats treated with a single injection of 3,5-T2 started 6-12 hours after infection with the maximal stimulation at 28-30 hours. By contrast injection of T3 increased resting metabolic rate that started 25-30 hours after injection and lasted 5-6 days. At the mitochondrial level stimulation is very rapid after injection of 3,5-T2, occurring within 1 hour.
In my parent application, now U.S. Pat. No. 6,534,676, I describe and claim the use of a thyroid hormone analog 3,5-diiodothyropropionic acid (DITPA) for treating patients with congestive heart failure. More particularly, as reported in my aforesaid U.S. Pat. No. 6,534,676, DITPA has been shown to improve left ventricular (LV) performance in post-infarction experimental models of heart failure when administered alone or in combination with an angiotension I-converting enzyme inhibitor. Cholesterol was significantly reduced in heart failure patients receiving DITPA after two and four weeks treatment, P<0.05 and P<0.1, respectively. In addition, it was noted that triglycerides were significantly reduced in these heart failure patients at two and four weeks of treatment with P<0.05 and P<0.005, respectively.
3,5-T2 and DITPA differ only in the side chain attached to the inner phenolic ring. In each case, the side chain consists of 3 carbons, ending in an amino acid group in 3,5-T2 and a carboxylic acid in DITPA. The structural similarity suggests the compounds should have some physiologic similarities. As reported in my aforesaid U.S. Pat. No. 6,534,676 normal volunteers and patients with heart failure indicate two such similarities: 1) There was significant weight loss in heart failure patients, who were obese and poorly conditioned, but no significant loss in volunteers who were more active and free of significant heart disease; and 2) Unexpectedly, there was a decrease not only in total cholesterol and LDL-cholesterol but also a highly significant decrease in triglycerides (P=0.005). A decrease in triglycerides also was seen with administration of 3,5-T2, but to my knowledge, has not previously been reported either with thyroid replacement in hypothyroidism or in the case of thyroid hormone analogs [13].